The goal of this project is to optimize these leads into very selective and metabolically stable compounds for further development into novel therapeutics. The overall benchmarks for this project are the development of compounds that are stable, soluble, brain-penetrant, orally bioavailable, and active in animal models of antipsychotic activity. During this period, several rounds of optimization for the lead ML1946 were carried out. Trade-offs in metabolic stability for potency were observed, and further work is being carried out to further balance these properties. For the ML321 lead, scale up of the intermediate scaffold is being carried out to enable further rounds of chemical optimization with the aim of increasing compound half-life.